Biology subjects

Neu, E.

Publications and source records attributed to Neu, E..

6 recordsLinked to original sources

bioRxiv2024

Structural basis for saxitoxin congener binding and neutralization by anuran saxiphilins

Dinoflagellates and cyanobacteria in harmful red tide algal blooms produce saxitoxin (STX) and [~]50 congeners that block voltage-gated sodium channel (NaV) function and disrupt bioelectrical signals1-4. Consuming seafood carrying these lethal toxins causes paralytic shellfish poisoning (PSP), a growing public health hazard due to climate change5-7 that motivates efforts to detect these toxins and counteract their noxious effects. Although structural studies of NaVs8,9 and anuran soluble STX binding proteins known as saxiphilins (Sxphs)10,11 revealed convergent binding modes for the bis-guanidinium STX core10,11, the structural basis for STX congener recognition is unknown. Here, we show that American bullfrog (Rana catesbeiana) RcSxph10,11 and High Himalaya frog (Nanorana parkeri) NpSxph10 use a pre-organized pocket to sequester STX congeners through a binding mode shared with STX. This lock and key recognition yields a tradeoff between a relatively rigid high-affinity toxin binding site in which bound waters are crucial and the ability of Sxphs to accommodate STX congener modifications. Importantly, functional studies show that Sxphs act as toxin sponges that reverse NaV block by multiple STX congeners and can detect these bis-guanidinium toxins in a radioligand receptor binding assay (RBA) for PSP toxin environmental testing12,13. Our findings establish how Sxphs sequester diverse neurotoxins and reveal structural factors underlying STX congener binding differences between Sxphs and NaVs that are rooted in the distinct toxin binding orientations on these two targets. These insights expand the molecular foundation required for understanding toxin sponge action and for guiding development of new means to monitor PSTs and mitigate their harmful effects.

biophysics↗

bioRxiv2023

The Effects of Preeclamptic Milieu on Cord Blood Derived Endothelial Colony-Forming Cells

Preeclampsia is one of the leading causes of infant and maternal mortality worldwide. Many infants born from preeclamptic pregnancies are born prematurely with higher risk of developing cardiovascular later in their life. A key mechanism by which these complications occur is through stress-induced dysfunction of endothelial progenitor cells (EPCs), including endothelial colony-forming cells (ECFCs). To gain insight into this, cord blood derived ECFCs isolated from preeclamptic pregnancies (PRECs) were analyzed and compared to their healthy counterparts. While PRECs preserve key endothelial markers, they upregulate several markers associated with oxidative stress and inflammatory response. Compared to ECFCs, PRECs also exhibit lower migratory behaviors and impaired angiogenic potential. Interestingly, treatment of neuropilin-1 can improve tube formation in vitro. Collectively, this study reports that preeclamptic milieu influence phenotypes and functionality of PRECs, which can be rejuvenated using exogenous molecules. Promising results from this study warrant future investigations on the prospect of the rejuvenated PRECs to improve lung function of infants born from preeclamptic pregnancies.

bioengineering↗

bioRxiv2023

Molecular epidemiology of Cercospora leaf spot on resistant and susceptible sugar beet hybrids

Cercospora leaf spot (CLS), caused by Cercospora beticola, is a major foliar disease impacting sugar beet production worldwide. The development of new resistant sugar beet hybrids is a powerful tool to better manage the disease, but it is unclear how these hybrids affect CLS epidemiology. We used a molecular epidemiology approach to study natural epidemics of CLS affecting two susceptible and two resistant sugar beet hybrids at two field sites. Infected plants were geotagged on a weekly basis. Isolations of C. beticola were made from infected leaves and genotyped using six simple sequence repeat loci to identify clones. We determined that CLS epidemics had a later onset in plots planted to resistant hybrids, but once the pathogen established an infection, there was little difference between resistant and susceptible hybrids in the probability of localized spread and dispersal. We found that different clones often infected the same leaf and that clusters of infected plants were often colonized by a mixture of clones. There was little overall difference in genetic diversity between resistant and susceptible hybrids, however genotypic evenness differed at one site. In this site we found one genotype restricted to the resistant cultivars at a high frequency. At the end of the epidemic infections were not randomly distributed across the fields and we found that a single clone could spread over a distance of 100 m during a growing season.

pathology↗

bioRxiv2023

Discovery of a functionally selective serotonin 5-HT1A receptor agonist for the treatment of pain

The G protein-coupled serotonin receptor 5-HT1AR mediates antinociception and may serve as a valuable target for the treatment of pain. Starting from a chemical library, ST171, a bitopic chemotype activating 5-HT1AR was evolved. In vitro pharmacological investigations of ST171 revealed potent and selective Gi activation (EC50 = 0.3 nM), with marginal Gs and {beta}-arrestin recruitment. Preclinical studies in mice showed that ST171 was effective in acute and chronic (inflammatory and neuropathic) pain models, without causing sedation. Comparison of cryo-EM structures of a 5-HT1AR-Gi complex bound to the functionally biased agonist ST171, with a structure bound to the functionally balanced agonist befiradol, showed that both ligands bind to the same orthosteric site, but address different exo-sites. The individual poses are associated with ligand-specific helical dispositions and rearrangements of microdomains. Complementation of these studies with molecular dynamics simulations allowed us to derive structural features associated with ST171s functional selectivity, a phenomenon that may be crucial to the discovery of more effective and safe GPCR drugs.

pharmacology and toxicology↗

bioRxiv2023

Genome-wide association studies reveal a rapidly evolving candidate avirulence effector in the Cercospora leaf spot pathogen Cercospora beticola

The major resistance gene BvCR4 recently bred into sugar beets provides a high level of resistance to Cercospora leaf spot caused by the fungal pathogen Cercospora beticola. The occurrence of pathogen strains virulent to BvCR4 was studied using field trials in Switzerland. Virulence of a subset of these strains was evaluated in a field trial conducted under elevated artificial disease pressure. We created a new C. bet cola reference genome and mapped whole genome sequences of 256 field-collected isolates. These were combined with virulence phenotypes to conduct three separate GWAS to identify candidate avirulence genes. We identified a locus associated with avirulence containing a single candidate avirulence effector gene named AvrCR4. All virulent isolates either lacked AvrCR4 or had non-synonymous mutations within the gene. AvrCR4 was present in all 74 isolates from non-BvCR4 hybrids, whereas 33 of 89 isolates from BvCR4 hybrids carried a deletion. We also mapped genomic data from 190 publicly available U.S. isolates to our new reference genome. The AvrCR4 deletion was found in only one of 95 unique isolates from non-BvCR4 hybrids in the U.S. AvrCR4 presents a unique example of an avirulence effector in which virulent alleles have only recently emerged. Most likely these were selected out of standing genetic variation after deployment of BvCR4. Identification of AvrCR4 will enable real-time screening of C. beticola populations for the emergence and spread of virulent isolates.

evolutionary biology↗

bioRxiv2018

A high-quality sequence of Rosa chinensis to elucidate genome structure and ornamental traits

Rose is the worlds most important ornamental plant with economic, cultural and symbolic value. Roses are cultivated worldwide and sold as garden roses, cut flowers and potted plants. Rose has a complex genome with high heterozygosity and various ploidy levels. Our objectives were (i) to develop the first high-quality reference genome sequence for the genus Rosa by sequencing a doubled haploid, combining long and short read sequencing, and anchoring to a high-density genetic map and (ii) to study the genome structure and the genetic basis of major ornamental traits.\n\nWe produced a haploid rose line from R. chinensis Old Blush and generated the first rose genome sequence at the pseudo-molecule scale (512 Mbp with N50 of 3.4 Mb and L75 of 97). The sequence was validated using high-density diploid and tetraploid genetic maps. We delineated hallmark chromosomal features including the pericentromeric regions through annotation of TE families and positioned centromeric repeats using FISH. Genetic diversity was analysed by resequencing eight Rosa species. Combining genetic and genomic approaches, we identified potential genetic regulators of key ornamental traits, including prickle density and number of flower petals. A rose APETALA2 homologue is proposed to be the major regulator of petals number in rose. This reference sequence is an important resource for studying polyploidisation, meiosis and developmental processes as we demonstrated for flower and prickle development. This reference sequence will also accelerate breeding through the development of molecular markers linked to traits, the identification of the genes underlying them and the exploitation of synteny across Rosaceae.

genomics↗